Dialkanoyloxybenzylidene dialkanoate

ABSTRACT

Disclosed herein are dialkanoyloxybenzylidene dialkanoate represented by the formula ##STR1## wherein X 1  and X 2  represent respectively alkanoyloxy group and a pharmaceutical composition in dosage unit form which comprises a dosage effective for the treatment of inflammatory disease of the dialkanoyloxybenzylidene dialkanoate as an active ingredient thereof.

This is a division of application Ser. No. 06/681,289, filed Dec. 13,1984 now U.S. Pat. No. 4,758,591.

BACKGROUND OF THE INVENTION

The present invention relates to a novel dialkanoyloxybenzeylidenedialkanoate represented by the formula (I): ##STR2## wherein x¹ and x²represent respectively alkanoyloxy group, and a pharmaceuticalcomposition in dosage unit form which comprises a dosage effective forthe treatment of inflammatory disease of a compound represented by theformula (I) and a pharmaceutially acceptable carrier.

Dihydroxybenzaldehyde has recently attracted attention as an antitumouragent (refer to Japanese Patent Application Laying-Open No.55-51018(1980)) and as an anti-inflammatory agent (refer to JapanesePatent Application Laying-Open No. 58-83619(1983)).

However, although dihydroxybenzaldehyde shows an excellentpharmacological activity in suppressing platelet aggregation andmigration of leukocytes at a relatively low concentration in vitro,owing to the rapid metabolism thereof in the living body, it isnecessary to administer a large amount thereof for a long time periodfor obtaining the effective effects of such pharmacological activity invivo, and there are difficulties in administering thereof due to thestimulus action and the oxidizability of the aldehyde moiety thereof.

As a result of the present inventors' studies for developing apharmaceutical agent which exhibits an effective pharmacologicalactivity when administered to a living body even at a small dose ratewhile scarcely showing side effects, the present inventors have foundthe compound synthesized by the reaction, for instance, between adihydroxybenzaldehyde and an alkanoic acid anhydride, which isrepresented by the formula (I): ##STR3## wherein x¹ and x² representrespectively alkanoyloxy group, and exhibits an effectivepharmacological activity while scarcely showing side effects.

In the formula (I), the two x¹ may occupy any of the following positionsin the benzene ring thereof.

(2,3), (2,4), (2,5), (2,6), (3,4) and (3,5).

The alkyl group of the alkanoyloxy group represented by x¹ and x²,respectively is a straight-chain or branched-chain alkyl group of from 1to 18 carbon atoms, and x¹ and x² are independently represented by theformulae, ##STR4## respectively.

SUMMARY OF THE INVENTION

In a first aspect of the present invention, there is provided adialkanoyloxybenzylidene dialkanoate represented by the formula (I):##STR5## wherein x¹ and x² represent respectively the same or differentalkanoyloxy group.

In a second aspect of the present invention, there is provided a processfor producing a dialkanoyloxy-benzylidene dialkanoate represented by theformula (I): ##STR6## wherein x¹ and x² represent respectivelyalkanoyloxy group, which comprises reacting a dihydroxybenzaldehyde withan alkanoic acid anhydride.

In a third aspect of the present invention, there is provided apharmaceutical composition in dosage unit form which comprises a dosageeffective for the treatment of inflammatory disease of adialkanoyloxybenzylidene dialkanoate represented by the formula (I):##STR7## wherein x¹ and x² represent respectively the same or differentalkanoyloxy group and a pharmaceutically acceptable carrier.

In a fourth aspect of the present invention, there is provided a methodfor the treatment of inflammatory disease, which comprises administeringto a patient suffering therefrom a pharmaceutically effective amount ofa dialkanoyloxybenzylidene dialkanoate represented by the formula (I):##STR8## wherein x¹ and x² represent respectively alkanoyloxy group.

BRIEF EXPLANATION OF DRAWINGS

Of the attached drawing, FIGS. 1, 3, 5 and 7 to 19 are the infraredabsorption spectra of the present substances Nos. 1, 2, 3 and 4 to 16according to the present invention, respectively, and

FIGS. 2, 4 and 6 are the nuclear magnetic resonance spectra of thepresent substances Nos. 1, 2 and 3, respectively.

DETAILED DESCRIPTION OF THE INVENTION

The novel dialkanoyloxybenzylidene dialkanoate represented by theformula (I) according to the present invention (hereinafter referred toas the present substance), the process for producing thereof and thepharmacological composition having an anti-inflammatory activitycomprising the present substance or containing the present substance asthe active ingredient thereof are explained as follows.

Although the present substance can be synthesized by reacting analkanoic acid anhydride with a dihydroxybenzaldehyde while heating amixture of the two reactants in the presence of a strong alkali such aspotassium hydroxide, sodium hydroxide and sodium acetate, the presentsubstance can be profitably synthesized in a high yield when thealkanoic acid anhydride (III) is reacted with a dihydroxybenzaldehyde(II) in the presence of a strong acid such as sulfuric acid,hydrochloric acid and nitric acid, as is shown by the following reactionformula. ##STR9## wherein the formula (I') represents the presentsubstance in which x¹ and x² are the same and represented by ##STR10##wherein m is an integer of 1 to 18.

Namely, to one mole of 2,3-; 2,4-; 2,5-; 2,6-; 3-4- or3,5-dihydroxybenzaldehyde represented by the formula (II), more than 3moles of the alkanoic acid anhydride represented by the formula (III)wherein m is an integer of from 1 to 18 are added, and after melting theanhydride at a temperature higher than the melting point of theanhydride and in a range of from room temperature to 100° C., acatalytic amount of a strong acid such as concentrated sulfuric acid,hydrochloric acid and nitric acid is rapidly added to the mixture whilestirring thereof. Then, the reaction exothermically proceeds to obtain ahomogeneous reaction mixture as a solution. The reaction completeswithin a time period of from one min to 5 hours, preferably from 2 minto one hour.

(2) In the case where x¹ and x² are different from each other, forinstance, x¹ represents ##STR11## wherein n is an integer of 1 to 18, x²represents ##STR12## a derivative represented by the formula: ##STR13##is reacted with an alkanoic acid anhydride represented by the formula##STR14##

From the thus obtained reaction mixture, the present substancerepresented by the formula (I') can be isolated by one of known methodssuch as recrystallization, extraction and removal of the by-producedalkanoic acid by extraction, evaporation of the un-reacted anhydride ofthe alkanoic acid or column-chromatography.

The above-mentioned synthetic process only shows one embodiment forobtaining the present substance and accordingly, the process forproduction of the present substance should not be limited to theabove-mentioned process.

Each of the present substances showed an activity of suppressing themigration of leukocytes, an activity of inhibiting the proliferation ofgranuloma and an activity of suppressing adjuvant arthritis as theresults of in vivo tests. In addition, each of the present substances isless toxic than the known substances such as dihydroxybenzaldehyde andis effective at a smaller dose rate than that of the known substancessuch as dihydroxybenzaldehyde. Accordingly, each of the presentsubstances has a pharmacological activity as an anti-inflammatory agent.

Namely, it is an ordinary anti-inflammatory agent, an anti-rheumaticagent against chronic arthritic rheumatism and an agent for treatingauto-immune diseases such as glomerular nephritis and systemic lupuserythematodes.

The mammalian toxicity and pharmacological properties of the presentsubstances are explained as follows by the following representativecompounds of the present substances. The other compounds are also usefulas the anti-inflammatory agent although some difference are seen amongthe activities thereof.

3,4-diacetoxybenzylidene diacetate, hereinafter referred to as thepresent substance No. 1,

2,3-diacetoxybenzylidene diacetate, hereinafter referred to as thepresent substance No. 2,

2,5-diacetoxybenzylidene diacetate, hereinafter referred to as thepresent substance No. 3,

3,4-dipropionyloxybenzylidene dipropionate, hereinafter referred to asthe present substance No. 4,

3,4-di-n-dodecanoyloxybenzylidene di-n-dodecanoate, hereinafter referredto as the present substance No. 5,

3,4-di-n-octadecanoyloxybenzylidene di-n-octadecanoate, hereinafterreferred to as the present substance No. 8 and

2,5-di-n-octadecanoyloxybenzylidene di-n-octadecanoate, hereinafterreferred to as the present substance No. 10.

(1) Acute Mammalian Toxicity

After dispersing each of the present substances Nos. 1, 4, 5, 8 and 10in an aqueous 0.2% solution of carboxymethylcellulose, the aqueousdispersion was orally administered to each of male Jcl-ICR mice. As aresult, LD₅₀ (acute, oral) of each of the tested substances was largerthan 4,000 mg/kg. LD₅₀ (acute, oral) of the present substances Nos. 2and 3 to male Jcl-ICR mice was larger than 2,000 mg/kg.

On the other hand, LD₅₀ (acute, oral) of 3,4-dihydroxybenzaldehyde tomale Jcl-ICR mice was 1503 mg/kg and accordingly, at least theabove-mentioned present substances were found to be extremely low inacute mammalian toxicity.

(2) Activity in Suppressing the Migration of Leukocytes

While using groups of male Donryu rate (six rats per group) andfollowing the carboxymethylcellulose-pouch method (refer to Ishikawa etal. Yakugaku Zasshi (Journal of the Pharmaceutical Society of Japan, 88,1472, 1968), the extent of inhibition of migration of polymorphonuclearleuckocytes to the site of inflammation by the present substance wasexamined. The specimen (the present substance) was dispersed in anaqueous 0.2% solution of carboxymethylcellulose and the dispersion wasadministered to each rat at a predetermined dose rate, and only theaqueous 0.2% solution of carboxymethylcellulose was administered to eachrat of control group. Test was carried out by injecting the aqueous 0.2%solution of carboxymethylcellulose into the pouch formed in the body ofthe rat and after 6 hours of the injection, the number ofpolymorphonuclear leukocytes in the exudate into the pouch was counted.The results are shown in Table 1, and as are seen in Table 1, it wasconfirmed that the present substance significantly suppressed themigration of polymorphonuclear leukocytes (PMN) to the site ofinflammation.

                  TABLE 1                                                         ______________________________________                                                                          Rate of                                     Group of   Dose     Number of     suppression                                 test       rate     PMN in exudate.sup.(1)                                                                      of migration                                animals    (mg/kg)  (mean ± SE)                                                                              of PMN (%)                                  ______________________________________                                        Control    --       10.2 ± 0.64                                                                              --                                          Group admin-                                                                  istered with                                                                  Present Sub-                                                                              5       6.0 ± 1.00**                                                                             41.2                                        stance No. 1                                                                             10        5.3 ± 0.47***                                                                           48.0                                                   50        4.9 ± 0.48***                                                                           51.9                                        Control    --       10.92 ± 0.81                                                                             --                                          Present Sub-                                                                             50       5.08 ± 0.28***                                                                           53.5                                        stance No. 4                                                                  Present Sub-                                                                             50       4.85 ± 0.43***                                                                           55.6                                        stance No. 5                                                                  Present Sub-                                                                             50       4.76 ± 0.54***                                                                           56.4                                        stance No. 8                                                                  Present sub-                                                                             50       6.23 ± 0.15***                                                                           42.9                                        stance No. 10                                                                 Administered with                                                                         5       6.83 ± 0.27***                                                                           37.5                                        Prednisolone                                                                  Administered with                                                                         5       7.02 ± 0.64**                                                                            35.7                                        Indomethacin                                                                  Administered with                                                                        50       7.92 ± 0.36*                                                                             27.5                                        3,4-dihydroxy-                                                                benzaldehyde                                                                  ______________________________________                                         Notes:                                                                        .sup.(1) (number of PMN/mm.sup.3 of the exudate) × 10                   *P < 0.05                                                                     **P < 0.01                                                                    ***P < 0.005                                                             

(3) Activity in Suppressing the Proliferation of Granuloma

While using groups of male Donryu rats in the fifth week after birth (5rats per group), the activity of the present substance is suppressingthe proliferation of granuloma was tested by the method of Fujimura(refer to Oyoyakuri (Pharmacometrics), 19(3) 329, 1980).

After soaking sheets of filter paper of 13 mm in diameter and 28 mg inweight into an aqueous 2% solution of carboxymethylcellulose containingboth dihydroxystreptomycin and penicillin, each of 10⁶ unit at therespective concentration of 0.1 mg/ml, each of the thus treated sheetswas buried subcutaneously into the back of each rat under anesthesia byether. Each specimen (the present substances) to be tested was dispersedin an aqueous 0.3% solution of carboxymethylcellulose and the dispersionwas administered orally to the thus treated rat after the rat had beenawaken from the anesthesia once a day for 10 days. After 11 days of thetreatment, granuloma formed in the rat was removed, dried for 24 hoursat 70° C. and weighed. To the rats of control group, only the aqueous0.3% solution of carboxymethylcellulose was orally administered once aday for 10 days, both results being shown in Table 2.

As are seen in Table 2, each of the tested present substancessignificantly suppressed the proliferation of granulating tissue formed.

                  TABLE 2                                                         ______________________________________                                                         Granuloma                                                    Group of    Dose       Dried       Rate of                                    test        rate       weight.sup.(1)                                                                            suppression                                animals     (mg/kg/day)                                                                              (mg)        (%)                                        ______________________________________                                        Control     --         88.1 ± 5.0                                                                             --                                         Present Sub-                                                                               5         50.4 ± 8.4**                                                                           42.8                                       stance No. 1                                                                              10         39.4 ± 3.0***                                                                          55.3                                                   50         34.0 ± 4.2***                                                                          61.4                                       Control     --         109.4 ± 7.5                                         Present Sub-                                                                              50         42.4 ± 5.7***                                                                          61.2                                       stance No. 4                                                                  Present Sub-                                                                              50         39.1 ± 3.4***                                                                          64.7                                       stance No. 5                                                                  Present Sub-                                                                              50         36.2 ± 2.6***                                                                          66.9                                       stance No. 8                                                                  Present Sub-                                                                              50         57.0 ± 6.7***                                                                          47.9                                       stance No. 10                                                                 Administered with                                                                          3         66.3 ± 8.4**                                                                           39.4                                       Indomethacin                                                                  Administered with                                                                          3         63.2 ± 8.6**                                                                           42.2                                       Prednisolone                                                                  Administered with                                                                         50         70.5 ± 9.7*                                                                            35.6                                       3,4-dihydroxy-                                                                benzaldehyde                                                                  ______________________________________                                         Notes:                                                                        .sup.(1) mean value ± standard error                                       *P < 0.05                                                                     **P < 0.01                                                                    ***P < 0.005                                                             

(4) Activity in Suppressing Adjuvant Arthritis

While using groups of female Jcl-SD rats in the 8th week after birth (6rats per group), the activity of the present substance is suppressingthe adjuvant arthritis was tested by the method of Fujihira et al.(refer to Oyoyakuri (Pharmacometrics), 5(2), 169, 1971).

Namely, Freund's complete adjuvant was implanted to the tail of each ratunder anesthesia by ether in an amount of 0.6 mg dissolved in 0.1 ml ofmineral oil, and after 2 weeks of the implantation, each specimen (thepresent substances) to be tested was orally administered once a day for20 days, and the state of the rat was observed.

As the results of the above-mentioned test, each of the presentsubstances tested, namely, Nos. 1, 2, 3, 4, 5, 8 and 10 showed anexcellent treating effect on the adjuvant arthritis caused by theimplanted Freund's complete adjuvant. On the other hand, in the ratsadministered with prednisolone, the increase of the body weight wassignificantly suppressed, and on the autopsy thereof, a significantatrophy of the thymus thereof was observed. In the rats administeredwith each of the present substance, suppression of increase of bodyweight and atrophy of the thymus were not observed. The findings confirmthat the present substance has scarcely the side effects.

Accordingly, the present substance is effective as an agent for treatingchronic inflammatory diseases such as rheumatism, etc.

As are seen in the above-mentioned test results, it can be recognizedthat the present substance has the excellent activities in suppressingthe proliferation of granuloma, in suppressing the adjuvant arthritisand in suppressing the migration of leukocytes and is extremely low inacute mammalian toxicity.

Accordingly, the present substance can be used in the extremelyimportant uses as an anti-inflammatory agent, an anti-chronic arthriticrheumatism and an agent for treating autoimmune diseases such assystemic lupus erythematodes and glomerular nephritis.

The present substance is possibly administered orally, intraintestinallyor in the form of injection in one of the various forms ofpharmaceutical formulation (so-called pharmaceutical composition) afterbeing combined with pharmaceutically acceptable carrier(s) and/oradjuvant(s). More than two of the present substances may be used incombination or after being mixed together, and the present substance maybe used after being combined with any other active ingredient forpharmaceutical use.

Since the present substance can be administered orally and parenterally,it can take any optional form of pharmaceutical compositions suitablefor the route of administration. In addition, the present substance maybe offered in the unit dose form, and as far as the pharmaceuticalcomposition contains an effective amount of the present substance, thecomposition can take the various forms such as powder, granule, tablet,sugar-coated tablet, capsule, suppository, suspension, solution,emulsion, ampoule and injection.

Accordingly, it should be recognized that the pharmaceutical compositioncomprising the present substance can be formulated by application of anyknown means for formulation of a pharmacologically active agent.

In addition, the content of the present substance as an activeingredient in the above-mentioned pharmaceutical composition can beadjusted in a broad range of from 0.01 to 100% by weight, preferably ina range of from 0.1 to 70% by weight.

As has been stated, although the pharmaceutical composition comprisingthe present substance is orally or parenterally administered to human ormammals, the oral administration including sublingual administration isparticularly preferable.

The parenteral administration includes subcutaneous-, intramuscular- andintravenous injection and instillation.

Since the dose rate of the present substance depends on the species, thesex, the age, the individual difference and the state of the disease ofthe patient to be administered therewith, there may be cases where anamount outside the following range is administered, however, in thecases where human being is the object of administration, the oral dailydose rate of one of the present substances is in a range of from 0.1 to500 mg/kg body weight, preferably in a range of from 0.5 to 200 mg/kgbody weight, more preferably in the range of from 3 to 100 mg/kg bodyweight, and the parenteral daily dose rate is is a range of from 0.1 to200 mg/kg body weight, preferably in a range of from 0.1 to 100 mg/kgbody weight, more preferably in the range of from 1.5 to 50 mg/kg bodyweight. The above-mentioned daily amount is divided equally into 1 to 4portions, and the thus divided portion is administered at a time (one tofour times per day).

The present invention will be explained more in detail while referringto the following non-limitative examples.

EXAMPLE 1 Synthesis of 3,4-diacetoxybenzylidene diacetate

(the present substance No. 1)

After introducing 30 g of protocatechualdehyde(3,4-dihydroxybenzaldehyde) and 92.4 g of acetic anhydride into a 200ml-flask and adding one drop of concentrated sulfuric acid to thecontent of the flask, the flask was shaken to rapidly induce a beginningof an exothermic reaction, thereby obtaining a uniform liquid reactionmixture of red in colour. After shaking the flask for 3 min, the liquidreaction mixture was poured into 500 ml of water to form a colourless,powdery crude product as a precipitate. The amount of the crude productafter collecting the precipitate by filtration and drying thereof was68.0 g (the yield: 96.6%). By subjecting the dried, crude product torecrystallization from a 2:1 mixed solvent of ethanol and ethyl acetate,59.9 g of colourless prisms (the yield: 85.0%) were obtained as theproduct of the process according to the present invention, the physicalproperties thereof being shown as follows:

    ______________________________________                                        (1)    Melting point: 129.0 to 130.0° C. (by capillary method)         (2)    Elementary analytical data:                                                                C (%)   H (%)                                             Found               55.70   4.90                                              Calcd. as C.sub.15 H.sub.16 O.sub.8                                                               55.56   4.97                                              (3)    Infrared absorption spectrum (by KBr-tablet method)                           The spectrum is shown in FIG. 1.                                       (4)    Nuclear magnetic resonance spectrum of .sup.1 H:                              The spectrum is shown in FIG. 2 with the following                            peaks:                                                                        δ(DMSOd.sub.6) ppm,                                                      ##STR15##                                                                    2.28(s): [ArOCOCH.sub.3, (6H)],                                               7.37 to 7.42(m): [ArH, (3H)],                                                  ##STR16##                                                             ______________________________________                                    

EXAMPLE 2 Synthesis of 2,3-diacetoxybenzylidene diacetate

(the present substance No. 2)

In the same procedures as in Example 1 except for using2,3-dihydroxybenzaldehyde instead of protocatechualdehyde in Example 1,the crude product of the objective substance was obtained, and byrecrystallizing thereof from ethyl acetate, a colourless powderysubstance was obtained as the present substance No. 2 in a yield of78.7%. The physical properties of the product are shown as follows.

    ______________________________________                                        (1)    Melting point: 108.5 to 109.5° C. (by capillary method)         (2)    Elementary analytical data:                                                                C (%)   H (%)                                             Found               55.70   4.80                                              Calcd. as C.sub.15 H.sub.16 O.sub.8                                                               55.56   4.97                                              (3)    Infrared absorption spectrum (by KBr-tablet method):                          The spectrum is shown in FIG. 3.                                       (4)    Nuclear magnetic resonance spectrum of .sup.1 H:                              The spectrum is shown in FIG. 4 with the following                            peaks.                                                                        δ(DMSOd.sub.6)                                                           ##STR17##                                                                     ##STR18##                                                                    7.37 to 7.59(m): [ArH, (3H)],                                                  ##STR19##                                                             ______________________________________                                    

EXAMPLE 3 Synthesis of 2,5-diacetoxybenzylidene diacetate

(the present substance No. 3)

In the same procedures as in Example 1 except for using2,5-dihydroxybenzaldehyde instead of protocatechualdehyde in Example 1,the crude product of the object substance was obtained, and byrecrystallizing the crude product from ethyl acetate, colourless prismwere obtained as the product according to the present invention in ayield of 81.3%. The physical properties of the thus recrystallizedproduct are shown as follows.

    ______________________________________                                        (1)    Melting point: 128.5 to 129.5° C. (by capillary method)         (2)    Elementary analytical data:                                                                C (%)   H (%)                                             Found               55.70   4.90                                              Calcd. as C.sub.15 H.sub.16 O.sub.8                                                               55.56   4.97                                              (3)    Infrared absorption spectrum (by KBr-tablet method):                          The spectrum is shown in FIG. 5.                                       (4)    Nuclear magnetic resonance spectrum of .sup.1 H:                              The spectrum is shown in FIG. 6 with the following                            peaks.                                                                        δ(in DMSOd.sub.6), ppm                                                   ##STR20##                                                                     ##STR21##                                                                    7.27 to 7.38(m): [ArH, (3H)],                                                  ##STR22##                                                             ______________________________________                                    

EXAMPLE 4 Synthesis of 3,4-dipropionyloxybenzylidene dipropionate

(the present substance No. 4)

After introducing 20.0 g of protocatechualdehyde(3,4-dihydroxybenzaldehyde) and 76.3 g of propionic acid anhydride intoa 200 ml-flask and adding one drop of concentrated sulfuric acid to themixture in the flask, the flask was shaken to rapidly induce thebeginning of an exothermic reaction, thereby obtaining a nearly uniformliquid reaction mixture of red in colour. After shaking the flask for 5min, the liquid reaction mixture was poured into 300 g of water toobtain a crude powdery product of whitish yellow in colour. Byrecrystallizing the thus obtained crude product from a mixed solvent ofmethanol and water, 45.9 g of colourless prisms product were obtained ina yield of 83.2%, the physical properties thereof being shown asfollows.

    ______________________________________                                        (1)    Melting point: 64.0 to 65.0° C. (by capillary method)           (2)    Elementary analytical data:                                                                C (%)   H (%)                                             Found               60.00   6.30                                              Calcd. as C.sub.19 H.sub.24 O.sub.8                                                               59.99   6.36                                              (3)    Infrared absorption spectrum (by KBr-tablet method):                          The spectrum is shown in FIG. 7.                                       (4)    Nuclear magnetic resonance spectrum of .sup.1 H:                              δ(in DMSOd.sub.6) ppm:                                                   ##STR23##                                                                    2.32 to 2.71(m): [OCOCH.sub.2, (8H)],                                         7.29 to 7.50(m): [ArH, (3H)],                                                  ##STR24##                                                             ______________________________________                                    

EXAMPLE 5 Synthesis of 3,4-didodecanoyloxybenzylidene didodecanoate

(the present substance No. 5)

After introducing 11.4 g of protocatechualdehyde and 127.8 g ofdodecanoic acid anhydride into a 500 ml-flask, the mixture was heated to80° to 85° C. to obtain a heterogeneous solution consisting of solidprotocatechualdehyde and liquefied dodecanoic acid anhydride. Afteradding one drop of concentrated sulfuric acid to the mixture, the thusformed mixture was shaken to rapidly induce an exothermic reaction,thereby obtaining a nearly homogeneous reaction mixture of reddish brownin colour. After heating the liquid reaction mixture for 40 min at 80°to 95° C., a mixed solvent of 500 ml of ethanol and 50 ml of ethylacetate was added to the reaction mixture, and the thus formed mixturewas cooled to room temperature and left for while to form scaly crystalsof white in colour as a precipitate. After collecting the crystals byfiltration, the crystals were dried to be 56.0 g of the white scalyproduct in a yield of 76.7%, the physical properties of the thusobtained white scaly crystals being shown as follows.

    ______________________________________                                        (1)   Melting point: 52.0 to 53.0° C. (by capillary method)            (2)   Elementary analytical data:                                                                   C(%)    H(%)                                            Found           :     74.80   11.20                                           Calcd. as C.sub.55 H.sub.96 O.sub.8                                                           :     74.61   10.93                                           (3)   Infrared absorption spectrum (by KBr-tablet method):                          The spectrum is shown in FIG. 8.                                        (4)   Nuclear magnetic resonance spectrum of .sup.1 H:                              δ(in DMSOd6) ppm:                                                        ##STR25##                                                                     ##STR26##                                                                     ##STR27##                                                                    2.46 to 2.66(m): [ArOCOCH.sub.2 R, (4H)],                                      ##STR28##                                                              ______________________________________                                    

EXAMPLE 6 Synthesis of 3,4-di-n-tetradecanoyloxybenzylidenedi-n-tetradecanoate

(the present substance No. 6)

In the same procedures as in Example 5 except for using n-tetradecanoicacid anhydride instead of dodecanoic acid anhydride in Example 5,crystals were obtained, and the crystals were recrystallized from amixed solvent (5:1) of ethanol and ethyl acetate to obtain a powderywhite product in a yield of 69.7%. The physical properties of the thusobtained product are shown as follows.

    ______________________________________                                        (1)   Melting point: 63.5 to 64.5° C. (by capillary method)            (2)   Elementary analytical data:                                                                   C(%)    H(%)                                            Found           :     76.00   11.60                                           Calcd. as C.sub.63 H.sub.112 O.sub.8                                                          :     75.85   11.32                                           (3)   Infrared absorption spectrum (by KBr-tablet method):                          The spectrum is shown in FIG. 9.                                        (4)   Nuclear magnetic resonance spectrum of .sup.1 H:                              δ(in CDCl.sub.3) ppm                                                     ##STR29##                                                                     ##STR30##                                                                     ##STR31##                                                                    7.14 to 7.42(m): [ArH, (3H)],                                                  ##STR32##                                                              ______________________________________                                    

EXAMPLE 7 Synthesis of 3,4-di-n-hexadecanoyloxybenzylidenedi-n-hexadecanoate

(the present substance No. 7)

In the same procedures as in Example 5 except for using n-hexadecanoicacid anhydride instead of dodecanoic acid anhydride in Example 5,crystals were obtained and by recrystallizing thereof from a mixedsolvent (2:1) of ethanol and ethyl acetate, a powdery white product wasobtained in a yield of 72.9%.

The physical properties of the thus obtained product are shown asfollows.

    ______________________________________                                        (1)   Melting point: 70.5 to 71.5° C. (by capillary method)            (2)   Elementary analytical data:                                                                   C(%)    H(%)                                            Found           :     76.90   11.70                                           Calcd. as C.sub.71 H.sub.128 O.sub.8                                                          :     76.84   11.63                                           (3)   Infrared absorption spectrum (by KBr-tablet method)                           The spectrum is shown in FIG. 10.                                       (4)   Nuclear magnetic resonance spectrum of .sup.1 H:                              δ(in CDCl.sub.3) ppm                                                     ##STR33##                                                                     ##STR34##                                                                     ##STR35##                                                                    7.13 to 7.43(m): [ArH, (3H)],                                                  ##STR36##                                                              ______________________________________                                    

EXAMPLE 8 Synthesis of 3,4-di-n-octadecanoyloxybenzylidenedi-n-octadecanoate

(the present substance No. 8)

In the same procedures as in Example 5 except for using n-octadecanoicacid anhydride instead of dodecanoic acid anhydride in Example 5,crystals were obtained and by recrystallizing the crystals from a mixedsolvent (2:1) of ethanol and ethyl acetate, a powdery white product wasobtained in a yield of 73.4%. The physical properties of the thusobtained product are shown as follows.

    ______________________________________                                        (1)   Melting point: 77.0 to 78.0° C. (by capillary method)            (2)   Elementary analytical data:                                                                   C(%)    H(%)                                            Found           :     77.40   12.10                                           Calcd. as C.sub.79 H.sub.144 O.sub.8                                                          :     77.65   11.89                                           (3)   Infrared absorption spectrum (by KBr-tablet method):                          The spectrum is shown in FIG. 11.                                       (4)   Nuclear magnetic resonance spectrum of .sup.1 H:                              δ(in CDCl.sub.3) ppm,                                                    ##STR37##                                                                     ##STR38##                                                                     ##STR39##                                                                    7.15 to 7.44(m): [ArH, (3H)],                                                  ##STR40##                                                              ______________________________________                                    

EXAMPLE 9 Synthesis of 2,5-di-n-dodecanoyloxybenzylidenedi-n-dodecanoate

(the present substance No. 9)

In the same procedures as in Example 5 except for using2,5-dihydroxybenzaldehyde instead of protocatechualdehyde in Example 5,crystals were obtained, and by recrystallizing the crystals from a mixedsolvent (2:1) of ethanol and ethyl acetate, a powdery white product wasobtained in a yield of 76.9%. The physical properties of the thusobtained product are shown as follows.

    ______________________________________                                        (1)   Melting point: 62.0 to 63.0° C. (by capillary method)            (2)   Elementary analytical data:                                                                   C(%)    H(%)                                            Found           :     74.50   11.00                                           Calcd. as C.sub.55 H.sub.96 O.sub.8                                                           :     74.61   10.93                                           (3)   Infrared absorption spectrum (by KBr-tablet method):                          The spectrum is shown in FIG. 12.                                       (4)   Nuclear magnetic resonance spectrum:                                          δ(in CDCl.sub.3) ppm,                                                    ##STR41##                                                                     ##STR42##                                                                     ##STR43##                                                                    7.11 to 7.33(m): [ArH, (3H)],                                                  ##STR44##                                                              ______________________________________                                    

EXAMPLE 10 Synthesis of 2,5-di-n-octadecanoyloxybenzylidenedi-n-octadecanoate

(the present substance No. 10)

In the same procedures as in Example 5 except for using2,5-dihydroxybenzaldehyde instead of protocatechualdehyde in Example 5and further using n-octadecanoic acid anhydride instead of dodecanoicacid anhydride in Example 5, crystals were obtained and byrecrystallizing the thus obtained crystals from a mixed solvent (2:1) ofethanol and ethyl acetate, a white powdery product was obtained in ayield of 82.8%. The physical properties of the thus obtained product areshown as follows.

    ______________________________________                                        (1)   Melting point: 84.0 to 85.0° C. (by capillary method)            (2)   Elementary analytical data:                                                                   C(%)    H(%)                                            Found           :     77.40   12.00                                           Calcd. as C.sub.79 H.sub.144 O.sub.8                                                          :     77.65   11.89                                           (3)   Infrared absorption spectrum (by KBr-tablet method):                          The spectrum is shown in FIG. 13.                                       (4)   Nuclear magnetic resonance spectrum of .sup.1 H:                              δ(in CDCl.sub.3), ppm,                                                   ##STR45##                                                                     ##STR46##                                                                     ##STR47##                                                                    7.11 to 7.33(m): [ArH, (3H)],                                                  ##STR48##                                                              ______________________________________                                    

EXAMPLE 11 Synthesis of 2,3-di-n-octadecanoyloxybenzylidenedi-n-octadecanoate

(the present substance No. 11)

In the same procedures as in Example 5 except for using2,3-dihydroxybenzaldehyde instead of protocatechualdehyde in Example 5,and further using n-octadecanoic acid anhydride instead of dodecanoicacid anhydride in Example 5, crystals were obtained, and byrecrystallizing the thus obtained crude crystals from a mixed solvent(5:1) of ethanol and ethyl acetate, a white powdery product was obtainedin a yield of 90.0%. The physical properties of the thus obtainedproduct, the present substance No. 11, are shown as follows.

    ______________________________________                                        (1)   Melting point: 64.0 to 65.0° C. (by capillary method)            (2)   Elementary analytical data:                                                                   C(%)    H(%)                                            Found           :     77.80   12.10                                           Calcd. as C.sub.79 H.sub.144 O.sub.8                                                          :     77.65   11.89                                           (3)   Infrared absorption spectrum (by KBr-tablet method):                          The spectrum is shown in FIG. 14.                                       (4)   Nuclear magnetic resonance spectrum of .sup.1 H:                              δ(in CDCl.sub.3), ppm                                                    ##STR49##                                                                     ##STR50##                                                                     ##STR51##                                                                    7.24 to 7.53(m): [ArH, (3H)],                                                  ##STR52##                                                              ______________________________________                                    

EXAMPLE 12 Synthesis of 3,4-di-n-butyryloxybenzylidene di-n-butyrate

(the present substance No. 12)

In a 300 ml-flask, 10 g of protocatechualdehyde and 43.3 g of butyricacid anhydride were introduced, and after adding one drop ofconcentrated sulfuric acid to the resultant mixture, the flask wasshaken for 10 min at room temperature to obtain a liquid reactionmixture of reddish brown in colour. After adding 200 ml of ethyl acetateto the liquid reaction mixture, the system was extracted five times witheach 80 ml of an aqueous 1N solution of sodium hydrogen carbonate forthe removal of butyric acid contained in the liquid reaction mixture.After washing the organic layer with an aqueous saturated solution ofsodium chloride, the thus washed organic layer was dried on anhydroussodium sulfate and decolorized by treatment with activated carbon andsubjected to evaporation under a reduced pressure to remove the solvent.The residue was subjected further to distillation under a reducedpressure by heating for the removal of still remaining butyric acidanhydride thereby obtaining a pale yellow oily product in a yield of97.4%. The physical properties of the thus obtained oily product areshown as follows.

    ______________________________________                                        (1)    Elementary analytical data:                                                                C (%)   H (%)                                             Found               63.10   7.40                                              Calcd. as C.sub.23 H.sub.32 O.sub.8                                                               63.29   7.39                                              (2)    Infrared absorption spectrum (by NaCl plate method):                          The spectrum is shown in FIG. 15.                                      (3)    Nuclear magnetic resonance spectrum                                           δ(in CDCl.sub.3), ppm,                                                   ##STR53##                                                                     ##STR54##                                                                     ##STR55##                                                                    7.15 to 7.46(m): [ArH, (3H)],                                                  ##STR56##                                                             ______________________________________                                    

EXAMPLE 13 Synthesis of 2,5-di-n-butyryloxybenzylidene di-n-butyrate

(the present substance No. 13)

In the same procedures as in Example 12 except for using2,5-dihydroxybenzaldehyde instead of protocatechualdehyde in Example 12,a pale yellow oily product, the present substance No. 13 was obtained ina yield of 97.5%. The physical properties of the product are shown asfollows.

    ______________________________________                                        (1)    Elementary analytical data:                                                                C (%)   H (%)                                             Found               63.50   7.10                                              Calcd. as C.sub.23 H.sub.32 O.sub.8                                                               63.29   7.39                                              (2)    Infrared absorption spectrum (by NaCl plate method):                          The spectrum is shown in FIG. 16.                                      (3)    Nuclear magnetic resonance spectrum of .sup.1 H:                              δ(in CDCl.sub.3), ppm,                                                   ##STR57##                                                                     ##STR58##                                                                     ##STR59##                                                                    7.12 to 7.37(m): [ArH, (3H)],                                                  ##STR60##                                                             ______________________________________                                    

EXAMPLE 14 Synthesis of 2,3-di-n-butyryloxybenzylidene di-n-butyrate

(the present substance No. 14)

In the same procedures as in Example 12 except for using2,3-dihydroxybenzaldehyde instead of protocatechualdehyde in Example 12,a pale yellow oily product, the present substance No. 14, was obtainedin a yield of 98.4%. The physical properties of the thus obtained oilyproduct are shown as follows.

    ______________________________________                                        (1)    Elementary analytical data:                                                                C (%)   H (%)                                             Found               63.50   7.20                                              Calcd. as C.sub.23 H.sub.32 O.sub.8                                                               63.29   7.39                                              (2)    Infrared absorption spectrum (by NaCl plate method):                          The spectrum is shown in FIG. 17.                                      (3)    Nuclear magnetic resonance spectrum of .sup.1 H:                              δ(in CDCl.sub.3), ppm,                                                   ##STR61##                                                                     ##STR62##                                                                     ##STR63##                                                                    7.12 to 7.54(m): [ArH, (3H)],                                                  ##STR64##                                                             ______________________________________                                    

EXAMPLE 15 Synthesis of 3,4-diacetoxybenzylidene dioctadecanoate

(the present substance No. 15)

In 100 ml-flask, 11.11 g of 3,4-diacetoxybenzaldehyde and 27.55 g ofstearic acid anhydride were introduced, and after heating the mixture at80° to 85° C. to obtain a homogenous solution, one drop of concentratedsulfuric acid was added to the solution and the mixture was reacted at80° to 85° C. for 20 min under agitation. After the reaction was over,the reaction mixture was dissolved in 150 ml of ethyl acetate whileheating the reaction mixture. The white powdery crystals were separatedfrom the reaction mixture after leaving the reaction mixture to cool,collected by filtration and dried to obtain 27.64 g of a product in ayield of 71.50%.

The thus obtained product showed the following properties.

    ______________________________________                                        (1)    Melting point: 75.0 to 76.0° C. (by capillary method)           (2)    Elementary Analytical Data:                                                                C (%)   H (%)                                             Found               73.30   10.70                                             Calcd. as C.sub.47 H.sub.86 O.sub.8                                                               73.01   10.43                                             (3)    Infrared absorption spectrum (by KBr-tablet method):                          The spectrum is shown in FIG. 18.                                      (4)    Nuclear magnetic resonance spectrum of .sup.1 H:                              δ(in CDCl.sub.3), ppm,                                                   ##STR65##                                                                     ##STR66##                                                                     ##STR67##                                                                    (10H)],                                                                       7.16 to 7.44(m): [ArH, (3H)],                                                  ##STR68##                                                             ______________________________________                                    

EXAMPLE 16 Synthesis of 3,4-dioctadecanoyloxybenzylidene diacetate

(the present substance No. 16)

In a 50 ml-flask, 10.2 g of 3,4-dioctadecanoylbenzaldehyde and 15.5 g ofacetic anhydride were introduced, and after dissolving the3,4-dioctadecanoylbenzaldehyde in acetic anhydride by heating themixture to 60° to 70° C., one drop of concentrated sulfuric acid wasadded to the thus obtained solution, and the flask was shaken toinitiate the reaction. A reaction exothermically proceeded to form areaction mixture uniform and pale brown in colour. After shaking thereaction mixture for 2 min, the reaction mixture was cooled to roomtemperature and 100 ml of purified water were added to the reactionmixture. The thus separated white powdery crystals were collected byfiltration and dried to obtain 11.73 g of a white powdery product in ayield of 99.8%. The product showed the following properties.

    ______________________________________                                        (1)   Melting point: 81.0 to 82.0° C. (by capillary method)            (2)   Elementary analytical data:                                                                   C(%)    H(%)                                            Found           :     73.00   10.60                                           Calcd. as C.sub.47 H.sub.86 O.sub.8                                                           :     73.01   10.43                                           (3)   Infrared absorption spectrum (by KBr-tablet method):                          The spectrum is shown in FIG. 19.                                       (4)   Nuclear magnetic resonance spectrum of .sup.1 H:                              δ(in CDCl.sub.3), ppm,                                                   ##STR69##                                                                     ##STR70##                                                                     ##STR71##                                                                     ##STR72##                                                                     ##STR73##                                                                     ##STR74##                                                              ______________________________________                                    

FORMULATION EXAMPLE 1 Preparation of powdery composition and capsularcomposition

Ten parts by weight of 3,4-dipropionyloxybenzylidene dipropionate (thepresent substance No. 4) 15 parts by weight of heavy magnesium oxide and75 parts by weight of lactose were uniformly mixed and the mixture waspulverized to obtain a powdery composition, and by capsulating the thusformed powdery composition into capsules, a capsular composition wasobtained.

FORMULATION EXAMPLE 2 Prearation of granular composition

Forty-five parts by weight of 3,4-didodecanoyloxybenzylidenedidodecanoate (the present substance No. 5), 15 parts by weight ofstarch, 16 parts of lactose, 21 parts by weight of crystallinecellulose, 3 parts by weight of polyvinyl alcohol and 30 parts by weightof water were uniformly mixed, and the mixture was well kneaded.

Thereafter, the kneaded mixture was pulverized, shaped into granularform and dried. The thus dried material was sifted to obtain a granularcomposition.

FORMULATION EXAMPLE 3 Preparation of an injection

Ten parts by weight of 3,4-diacetoxybenzylidene diacetate (the presentsubstance No. 1), 3 parts by weight of benzyl alcohol and 87 parts byweight of an aqueous physiological saline solution were mixed underheating, and the thus heated uniform mixture was sterilized to obtain aninjection.

What is claimed is:
 1. A process for producing adialkanoyloxy-benzylidene dialkanoate of the formula (I): ##STR75##wherein X¹ and X² are an alkanoyloxy group having from 1 to 18 carbonatoms, which comprises the step:(i) reacting a dihydroxybenzaldehydewith an alkanoic acid anhydride of the formula (C_(m) H_(2m+1) --CO)₂ O,wherein m is an integer of 1 to 18 in the presence of base with heatingor in the presence of strong acid.
 2. A process for producing adialkanoyloxy-benzylidene dialkanoate of the formula (I): ##STR76##wherein X¹ and X² are, independently, an alkanoyloxy group having from 1to 18 carbon atoms, which comprises the steps:(i) reacting adihydroxybenzaldehyde with an alkanoic acid anhydride of the formula(C_(n) H_(2n+1) --CO)₂ O, wherein n is an integer of 1 to 18, to obtaina dialkanoyloxybenzaldehyde of the formula (II): ##STR77## (ii) reactingsaid dialkanoyloxybenzaldehyde with an alkanoic acid anhydride of theformula (C_(m) H_(2m+1) --CO)₂ O, wherein m is an integer of 1 to 18, inthe presence of base with heating or in the presence of strong acid. 3.The process according to claims 1 or 2, wherein said base in one memberselected from the group consisting of potassium hydroxide, sodiumhydroxide, and sodium acetate.
 4. The process according to claims 1 or2, wherein said strong acid is one member selected from the groupconsisting of sulfuric acid, hydrochloric acid, and nitric acid.